Iontophoresis is defined by Dorland's Illustrated Medical Dictionary as "the introduction, by means of electric current, of ions of soluble salts into the tissues of the body for therapeutic purposes." Iontophoretic devices have been known since the early 1900's. British patent specification No. 410,009, published in 1934, describes an iontophoretic device that overcame one of the disadvantages of such early devices known to the art at that time, namely the requirement of a special low tension (low voltage) some of current which meant that the patient needed to be immobilized near such source. In that British specification, the device was made by forming a galvanic cell from two electrodes plus the material containing the medicament or drug to be transdermally delivered. The galvanic cell produced the current necessary for iontophoretically delivering the medicament. This ambulatory device thus permitted iontophoretic drug delivery with substantially less interference with the patient's daily activities.
The iontophoresis process has been found to be useful in the transdermal administration of medicaments or drugs including lidocaine hydrochloride, hydrocortisone, fluoride, penicillin, dexamethasone sodium phosphate and many other drugs. Perhaps the most common use of iontophoresis is in diagnosing cystic fibrosis by delivering pilocarpine salts iontophoretically. The pilocarpine stimulates sweat production; the sweat is collected and analyzed for its chloride content to detect the presence of the disease.
Presently known iontophoretic devices use at least two electrodes, positioned in intimate contact with some portion of the skin of the body. A first electrode, called the active or donor electrode, delivers the ionic substance, medicament, drug precursor or drug into the body by iontophoresis. The second electrode, called the counter or return electrode, closes an electrical circuit including the body, the first electrode and a source of electrical energy, such as a battery. For example, if the ionic substance to be driven into the body is positively charged, the anode will be the active electrode and the cathode will serve as the counter electrode to complete the circuit. If the ionic substance to be delivered is negatively charged, the cathode will be the active electrode and the anode will be the counter electrode.
Alternatively, both the anode and cathode may be used to deliver drugs of opposite electrical charge into the body. In this situation, both electrodes are considered to be active or donor electrodes. For example, the anode can drive a positively charged ionic substance into the body, and the cathode can drive a negatively charged ionic substance into the body.
It is also known that iontophoretic delivery devices can be used to deliver an uncharged drug or agent into the body. This is accomplished by a process known as electroosmosis. Electroosmosis is the transdermal flux of a liquid solvent (e.g., the liquid solvent containing the uncharged drug or agent) that is induced by the presence of an electrical field imposed across the skin by the donor electrode. As used herein, the terms "iontophoresis" and "iontophoretic" refer to (1) the delivery of of charged drugs or agents by electromigration, (2) the delivery of uncharged drugs or agents by electroosmosis, (3) the delivery of charged drugs or agents by the combined processes of electromigration and electroosmosis, and/or (4) the delivery of a mixture of charged and uncharged drugs or agents by the combined processes of electromigration and electroosmosis.
Existing iontophoresis devices generally require a reservoir or source of the ionized or ionizable species, or a precursor of such species, that is to be iontophoretically delivered or introduced into the body. Examples of such reservoirs or sources of ionized or ionizable species include a pouch as described in the previously mentioned Jacobson patent, U.S. Pat. No. 4,250,878, issued to Jacobsen, or a pre-formed gel body as disclosed in U.S. Pat. No. 4,383,529, issued to Webster. Such reservoirs are electrically connected to the anode or the cathode of an iontophoresis device to provide a fixed or renewable source of one or more desired species.
Recently, transdermal delivery of peptides and proteins, including genetically engineered proteins, by iontophoresis has received increasing attention. Generally speaking, peptides and proteins being considered for transdermal or transmucosal delivery have a molecular weight ranging between about 500 to 40,000 Daltons. These high molecular weight substances are too large to passively diffuse through skin at therapeutically effective levels. Because many peptides and proteins carry either a net positive or net negative charge, but are unable to passively diffuse through skin, these substances are considered likely candidates for iontophoretic delivery.
Iontophoresis is now being considered for long term delivery, over periods of longer than 24 hours, of a number of drugs, including peptides and proteins (e.g., insulin). As the length of delivery increases, there is a need to develop small unobtrusive iontophoretic delivery devices which can be easily worn on the skin under clothing. One example of a small iontophoretic delivery device designed to be worn on the skin is disclosed in U.S. Pat. No. 4,474,570, issued to Ariura et al. Devices of this type are powered by small, low voltage batteries. In addition to the need for developing smaller iontophoretic delivery devices, there is a need to reduce the cost of these devices in order to make them more competitive with conventional forms of therapy such as pills and subcutaneous injections.
One method of reducing cost is to use even lower voltage power sources. Unfortunately, as the power source voltage decreases, the drug delivery rate also decreases. Thus, there is a need for a method of improving the performance characteristics, such as the amount of drug delivered per unit of power, of iontophoretic delivery devices to enable the use of inexpensive low-voltage power sources. Further, a particular need exists for monitoring the amount of medicament delivered, especially when the amount delivered can vary or does not follow a predetermined pattern, as in a patient-controlled (on-demand) and feedback-controlled delivery system.
One method of increasing the rate at which drug is delivered from a transdermal iontophoretic drug delivery device is to apply the device on a skin site having optimum drug transport characteristics. For example, in International Patent Publication No. WO 91/08795, R. P. Haak et al discuss optimum skin sites for attaching an iontophoretic drug delivery device to a human patient. In a human patient, the patient's back appears to be the optimum site for electrically assisted drug delivery, although the back does not have the highest density of sweat ducts or skin pores for iontophoretic transport.
During long-term iontophoretic drug delivery, it is difficult to accurately estimate beforehand the amount of drugs that will be delivered by iontophoresis over a selected time interval such as 24 hours. For example, either by design or because of uncontrollable factors, such as battery discharge characteristics, the current used to drive the iontophoresis process may vary over this time interval. Further, environmental conditions, such as humidity, temperature, perspiration and wetness, due to bathing, adjacent to the delivery site may also vary with time. Either of these uncertainties may produce uncertainties in the amount of drug or medicament absorbed by the body over a long time interval.
Some workers have attempted to handle these uncertainties by providing feedback regulation or polarity reversal of the applied voltage so that the current, and thus the rate of delivery of drug/medicament by iontophoresis, is kept approximately uniform over a selected time interval. Polarity is sometimes reversed to avoid skin irritation and to depolarize the skin. Skin polarization is an obstacle to efficient electrotransport drug delivery. Polarity control is disclosed in U.S. Pat. No. 4,116,238, issued to Pettijohn, in U.S. Pat. No. 4,141,359, issued to Jacobsen, et al., in U.S. Pat. No. 4,406,658, issued to Lattin, et al., and in U.S. Pat. No. 4,456,012, issued to Lattin. The complex electronics required here uses devices such as transformers and SCR rectifiers, and it may not be convenient or even possible to provide this in a compact, lightweight package that can be worn by the patient under clothing.
Other workers have provided means for selectively varying the current delivered by the applied voltage near the site. McNichols et al., in U.S. Pat. No. 4,725,263, disclose use of a current control module for iontophoresis that can be mechanically trimmed in order to change the current level used for this process. However, only a small number, such as three, preselected current values may be chosen, and the choice of current level usually cannot be reversed. The mechanical trimming also serves as a simple visual indicator of which current level has been chosen.
Sibalis discloses provision of a third electrode in a parallel current loop in the iontophoresis process, in U.S. Pat. No. 4,708,716. This parallel current loop provides a feedback signal that assertedly indicates when a desired dosage level is achieved in the blood serum. A reverse plating cell is used here, in which the resistance to current flow from anode to cathode increases abrupdy as metal or another electrically conductive material is transferred (with the accompanying electrical charge) from an active electrode to a counter electrode. However, this indicator, which relies on an abrupt increase in resistance to charge flow, appears to provide only two indicator levels.
An electronic control system for limiting total iontophoretic dose is disclosed by Tapper in U.S. Pat. No. 4,822,334. The system includes a voltage controlled osciallator whose oscillation frequency is proportional to the current delivered to a load, such as a patient's body that is receiving the dose. The number of VCO cycles in a given time interval is counted to determine the load current presently applied to and the dose delivered during that time interval.
U.S. Pat. No. 4,942,883, issued to Newman, discloses use of a sensing means in a housing for an iontophoretic device to alternatingly turn on and turn off the current that delivers the drug or medicament. The frequency of alteration of current turn on and turn off may be of the order of 50 kHz, and may be controlled by an on-board microprocessor.
The devices discussed above are often bulky and do not provide a continuous indicator of cumulative dose delivered by iontophoresis. What is needed is a compact, lightweight iontophoretic apparatus that provides a continuous indicator of cumulative dose delivered and, perhaps, of the status of certain other system variables, and that can easily be worn adjacent to the delivery site for the drug, medicament or other therapeutic agent